Inherited mutations of the BRCA1 gene are major contributors to hereditary breast and ovarian cancer [1] [2] [3] [4] [5]. However, the mechanisms by which BRCA1 acts as a tumor suppressor are only partially understood [1] [6] [7]. The ability of BRCA1 protein to activate transcription may allow BRCA1 to regulate the cell cycle [8] [9]. Overexpression of BRCA1 blocks growth of breast and ovarian cancer cell lines [10]. Moreover, BRCA1 associates with Rad51, which is important for efficient DNA recombination [11] [12], both in mitotic and meiotic cells [13], suggesting a role for BRCA1 in the preservation of genome integrity [1].
BRCA1 is a co-activator of transcription, given that it is part of the RNA polymerase II holoenzyme and that it functions as a transactivator [7] [9] [13] [14] [15]. Because the tumor suppressor p53 [16] [17] plays a major role in DNA repair processes [18] as well as in the cell cycle arrest triggered by DNA damage [19] [20] [21], characterizing the interactions between BRCA1 and p53 are relevant, particularly under conditions that induce DNA damage, for understanding hereditary breast and ovarian cancer.
Zhang et al [15] reported that BRCA1 (amino acids 224-500) interacts physically with p53 (amino acids 300-393) and that stimulates p53-transactivation and apoptosis. This interaction was identified only in vitro, and cell experiments have not been done with mutations or deletions of this BRCA1 region, nor using mammary or ovarian cells. Moreover, both the p53 C-terminus (amino acids 311-393), which contains the tetramerization domain, and the p53 basic region (amino acids 355-393) bind to BRCA1 (amino acids 224-500) domain with relatively weak affinity [22]. Therefore, it is not clear how biologically relevant is the binding of the BRCA1 (224-500) with the p53 C-terminal domain [22].
Computer analysis has suggested the presence of a probable p53 binding domain in the C-terminus of BRCA1 (BRCT) [23] [24], a module present in proteins involved in DNA repair [25], since it is analogous to the p53 binding domain of 53BP1 [23] [26]. Although it has been also reported that the second BRCT domain of BRCA1 protein may interact with p53 [27], quantitative biophysical measurements indicate that this region of BRCA1 does not bind to p53 [28]. Thus, it is uncertain whether these regions (or others) within BRCA1 reported to interact with p53 [15] [27] are critical for the apoptotic and transactivation effects of BRCA1 [15] [28].